Aortic aneurysms and dissections are the major diseases affecting the aorta, and a leading cause of morbidity and mortality in the United States. Thoracic aortic aneurysms progressively enlarge over time, leading to life-threatening type A dissections (TAAD) in the absence of prophylactic surgical repair. TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance in up to 19% of TAAD patients. We mapped the first locus for the condition, the TAAD1 locus at 5q13-14, which is responsible for approximately 10-30% of familial disease, and proceeded to map a second locus for TAAD, the TAAD2 locus at 3p24-25, responsible for approximately 5% of familial disease. Clinical studies have delineated differences in the phenotype in families linked to TAAD1 versus TAAD2. Recently, we have determined that the defective gene at the TAAD2 locus encodes the transforming growth factor p receptor type II, suggesting that dysregulation of the TGFp pathway may be a mechanism leading to aneurysms. In 30% of our TAAD families, linkage of the phenotype to markers at known loci is excluded, providing evidence that one or more loci for the disease are yet to be identified. We hypothesize that there are multiple genes responsible for familial TAAD, and differences in the phenotype will distinguish families with disease due to mutations in the various genes. The long-term goal of the proposed project is to identify the genes that cause familial TAAD and characterize, the associated phenotype. The first aim is to identify, characterize and collect samples from TAAD families. We have identified 278 families with 2 or more members with TAAD, and we propose to continue to recruit families with a focus on large families with multiple living, affected members. Aim 2 will map a third locus for familial TAAD (TAAD3) using samples from a single family with multiple affected members. We have identified a four generation family in whom the phenotype is not linked to known loci that will be used to map this novel locus. Aim 3 proposes to use the following two stage mapping strategy to identify another major locus responsible for 20-30% of familial TAAD: (1) affected relative pair (ARP) linkage analysis using 2 samples from affected individuals from 100 unrelated TAAD families; (2) fine mapping using the entire cohort. The final aim is to refine and narrow the critical interval at the TAAD1 locus using a shared SNP haplotype mapping strategy and identify the defective gene within the critical region. Through these specific aims, we will map novel loci for TAAD and identify further gene(s) causing the disease. If thoracic aortic aneurysms are diagnosed, followed medically, and surgically repaired prior to dissection, the life expectancy of the affected individual is significantly improved. Therefore, identification of the genes that predispose individuals to TAAD is critical in preventing premature deaths due to dissections.